This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Worldwide, the vast majority of HIV-1 cases occur through heterosexual transmission. However, the earliest initial events involved in vaginal transmission are uncertain. We have been working with Tom Hope using photoactivateable virus, dyes, or compounds designed to test the mechanisms of viral penetration into the vaginal mucosa. The results prove that HIV enters intact vaginal squamous epithelium by passive diffusion through multiple layers of squamous epithelial cells. Our most recent data indicate it is actually the CD4+ T Cells in the vaginal mucosal that support the earliest events in transmission, and dendritic cells play a minimal, if any, role in the early events involved in vaginal transmission. These studies were started as a collaborative, multicenter trial with the Center for HIV and AIDS vaccine Initiative (CHAVI) but now that these earliest events are known, we are now trying to determine how the virus gets from the vaginal mucosal to the intestinal tract in the first few days of infection using R01AI084793.